Alcohol is a well established risk factor for injury and is present in approximately 40% of trauma victims. In addition to the increased incidence of injury, alcohol intoxication contributes to alterations in initial assessment, management and outcome resulting in an overall more complicated clinical course. Mirroring clinical observations, previous studies from our lab and others have consistently demonstrated impaired counterregulatory response to hemorrhagic shock (HS) during acute alcohol intoxication (AAI), as evidenced by greater hypotension in response to blood loss, impaired blood pressure recovery during fluid resuscitation (FR), and blunted neuroendocrine response. In addition, AAI has been shown to modulate the inflammatory and immune responses during the early recovery as well as increased mortality in AAI-intoxicated animals in response to bacterial pneumonia during the recovery period Investigations into the mechanism of the AAI- induced impairment of hemodynamic and neuroendocrine response indicate that this detrimental impact of AAI is not insurmountable and have led to the proposal of potential alternatives to conventional resuscitation techniques that may prove beneficial and necessary in the intoxicated trauma victim. While the debate surrounding the most appropriate resuscitation fluid is hindered by the varying presentations of trauma victims, those suffering injury during AAI have a distinct profile of deficiencies as compared to their sober counterparts thus providing a basis by which to suggest specific alternative resuscitation techniques for this subpopulation. Fluid resuscitation, once considered innocuous volume replacement, is now understood to contribute greatly to patient outcome. Of particular interest, and gaining more support recently, is the use of hypertonic saline (HTS). Resuscitation with HTS has been shown to provide numerous benefits including survival, blood pressure recovery, tissue perfusion and immune function. Many of these benefits target deficits observed in the intoxicated hemorrhage victim, suggesting the potential for even greater improvement with utilization of HTS in this population. Thus, we hypothesize that small volume hypertonic fluid resuscitation from hemorrhagic shock during acute alcohol-intoxication will 1) improve hemodynamic recovery, 2) decrease organ damage, and 3) improve the host defense during recovery. The hypothesis will be critically tested utilizing an established rodent model of acute alcohol intoxication and hemorrhagic shock. The results of these studies will provide a better understanding of how acute alcohol intoxication alters the response to fluid resuscitation, as well as providing the basis for selective treatment for this critical population of patients. PUBLIC HEALTH RELEVANCE: The goal of these studies is to investigate the mechanisms of the impaired response to fluid resuscitation following blood loss in the intoxicated individual and develop therapeutic targets aimed at improving both initial and long-term outcome following traumatic injury in this population.